Study type (S): randomized clinical trials To identify trials to be included for this review, we searched

were used in the meta-analysis of each outcome. We calculated the means difference and the 95 % confidence

interval (IC). Heterogeneity was assessed using the Cochran Q test and I2statistics. The quality of the evidence was graded for each outcome across studies (body of evidence) using the Grading of Recommendations: Assessment, Development and Evaluation (GRADE) to determine the overall strength of evidence for each meta-analysis. The GRADE approach is used to contextualize or justify intervention recommendations with four levels of evidence quality, ranging from high to very low. The GRADE approach begins with the study design (RCTs or observational studies) and then addresses five reasons (risk of bias, imprecision, inconsistency, indirectness of evidence, and publication bias) to possibly rate down the quality of the evidence (1 or 2 levels) and three to possibly rate up the quality (large effect; management of confounding factors; dose-response gradient). Each one of these topics was assessed as “no limitation”; “serious limitations” and “very serious limitations” to allow categorization of the quality of the evidence for each outcome into high, moderate, low, and very low. The “high quality” suggests that we are very confident that the true effect lies close to the estimate of the

effect. On the other extreme “very low quality” suggests that we have very little confidence in the effect estimate and the estimate reported can be substantially different from what it was measured.

Results:

After the database screening and removal of duplicates, 1741 studies were identified (Figure 1). After title screening, 62 studies remained. This number was reduced to 13 after

examination of the abstracts and their full texts were assessed

to check eligibility. Among them, 4 were excluded because: i) Botox was also used in the control group [21]; and ii) not checked the intensity of myofascial pain [22-24].

Characteristics of included articles

Thecharacteristicsofthe9selected studiesarelisted in Table

2 and Table 3. Three studies used the cross-over [25-27] design e 6 studies parallel design [28-33]. The studies were performed in different countries, 2 were performed in Canada [25, 26], and one study in other countries: Saudi Arabia [28], Brazil [29], Sweden [27], Italy [30], India [31], Germany [32] and US [33]. The mean age of the participants included in the clinical trials was approximately 44 years; however, this information was not reported in 4 studies [25, 30-32]. The percentage of males was 16 % in 6 studies [25-27,29, 30, 33], but this information was not reported in 3 studies [28, 31, 32].

Table 2- Summary of the studies selected for this systematic review.

Study ID Study design Cou ntry

Study Outcome Subjects’ age mean ± SD [range] (years) No. of male subj ects [%] Total No. patient s [dropouts] Interven tion Group [brand] BTX-A units (U) Control Group [brand] Diagnostic methods

Al-Wayli 2017 (28) Parallel Saud i Arab ia Evaluate the role of BTX-A in the Treatment of pain associated with nocturnal bruxism 45.5 ± 10.8 (2060) n.r. T = 50 I = 25 C = 25 [n.r.]

De Carli et al 2016(29) Parallel Braz il Compare the use of low-level laser and BTX-A in the treatmentofmyofasci alpainandwhetherthe halterthemouthopeni ngofpatientswithtem poromandibulardiso rder 38

n.r. 13 T = 18

I = 7

C = 8

[0] BTX-A (Botox, Allergan Inc.)

Botulim toxin

n.r. 20 U per side (3 points each masseter) T= 40 U

First, 30 U per point (2 in the masseter muscle and 1 in the temporal muscle). Fifteen days later 15 U per point

T = 500 U Tradicional methods[resurance and detailed explanation of the nature of thedisease, occlusal splints and pharmacologic measures]

Low-level laser therapy with GaAlAs, l = 830 nm, dose = 80 J/cm2 per point ( 2 points in the masseter muscle and 1 point in the temporal muscle).Seven applications within 48-h intervals Bruxism [questionnarie (n.r.) clinical examination (n.r) signs and symptoms]

Clinical examination (n.r.) signs and symptoms

Ernberg et al 2011 (27) Crossover

Graboski et al 2005 (26) Crossover Swe den

Can ada Efficacy of BTX-A was inpatients with persistent myofascial Temporo mandibular disorders (TMD) 38 ± 12 (n.r.) 9.5 T = 21 I = 12 C = 9 [0]

Compare the effectiveness of trigger point injections using BTX A versus bupivacaine, both in 5.1 ± 13.4 (n.r.) 47 T = 18 I = 9 C = 9 [1]

BTX-A (Botox; supplied by Allergan Norden AB, Uppland sVäsby, Sweden)

BTX-A [n.r.] 10 U (0.1 ml) per point. There are 3 points, in the deep posterior portion, in the origin and attachment of masseter muscle. T= 50 U (unilateral) / 100 U (bilateral) Saline solution 0.1 ml per point. There are 3 points, in the deep posterior portion, in the origin and attachment of masseter muscle. RDC/TMD

25 U per trigger point T = n.r. Bupvacaine 0.5% [n.r.] ; ½ cc per trigger point Clinical examination for pain by physiatrist

combination with a home-based habilitation program

GuardaNardini et al 2012(30) Parallel Italy Effectiveness of BTX-A Injections And physiatric treatment provided by means of Fascial Manipulation techniques in the management of my fascial pain of jaw muscles n.r. (23-69)

I = 47.7 + 14.3 C = 43.2 + 13.9 8 [26] T = 30 I = 15 C = 15 [n.r.] BTX-A (Dysport , Ipsen, Ltd., UK) Total of 150 U per side. Fiveinjections minimum with a reverse pyramid pattern was performed in the masseter muscles, and a chess-board pattern was used for the temporal is muscles

Fascial Manipulation by therapists (deep digital pressure). Three (±1) 50 min sessions on a week.

RDC/TMD

Jadhao et al 2017 (31) Parallel Indi a Evaluate the effect of BTX-A in the treatment of myofascial pain and the occlusal force characteristics of masticatory muscles n.r. (20–35) n.r. T = 24

I = 8

C = 8

P = 8

[n.r.] BTX-A (Botox,

Allergan , Inc., Irivine, CA, USA) Intramuscular injections for each side (30 U) with in the masseter muscles and three injections (20 U) with in the anterior temporalis muscles, for a treatment total of 100 U Saline solution injections: the same of I.

P: no injections were given Clinical examination and bed partner

Von Lindern et al 2003(32) Parallel Ger man y

Nixdorf et al 2002 (25) Crossover Can ada

Ondo et al 2018 (33) Parallel EU A Assess whether the targeted reduction of masticatory muscular hyperactivity by local injection treatment with BTXA can improve facial pain headache symptoms

BTX-A was efficacious for the treatment of chronic moderate to severe jaw muscle pain in females n.r. n.r. T = 90

I = 60

C = 30

[n.r.]

n.r. 33 (18 45) 0 T = 30 I = 15 C = 15 [17] BTX-A (Botox; Allergan , Ettlinge n, German y) 35 U in 0.7 mLof NaCl saline injected in The corresponding muscles (M. masseter, M. temporalis, M. perygoideus medialis) 0.7 mL of saline solution injections: the same of I. Clinical examination and standardized questionnaire

BTXA(Botox ; Allergan , Markha m ON, Canada) 25 U of 0.6 cm3 in each temporalis and 50 U of 0.6 cm in each masseter divided in three points 0.9% normal saline in the same points RDC/TMD

Safety and efficacy of BoNT-A injections into the masseter and temporalis muscles in patients with symptom mastic sleep bruxism. 47.4 ± 16.9 (18 85) 17 T = 23 I = 13 C = 10 [1] BoNTA, Botox, Allergan , Irvine, CA) 100 U/mL. Sixty units were Injected bilaterally into the masseter muscles (2 sites) and 40 units into the bilateral temporalis (3 sites) with anatomic/palpatio n localization with n.r. The same of I. Physical examination in questionnaire with a modified quantifiable portion (G. Lavigne)